Our recent work has demonstrated that the immunosuppressive drug rapamycin selectively affects the CsA-resistant pathway. Our initial studies have focused on the mechanism of activation of the IL-2 gene in a CsA-resistant manner. We found that the effect of rapamycin on the IL-2 expression was due to alteration in IL-2 mRNA stability. More recently, we have also shown that activation of T cells by IL-12 is resistant to CsA, but sensitive to rapamycin. As the intracellular target of rapamycin is mTOR (mammalian target of rapamycin), we are investigating the mechanism of activation of mTOR during T cell activation. Regarding the physiological role of the resistant pathway, we have observed the effect of cytokine signaling, particularly the combination of IL-12 and IL-18 but not individual cytokine alone, in activating resting human peripheral blood T cells in producing IFN-&#61543;&#61472;in a CsA-resistant, but rapamycin-sensitive manner. Interestingly, nave CD4+ T cells are more responsive to IL-12 plus IL-18 stimulation in comparison to memory CD4+ T cells. This cytokine-mediated activation of resting T cells is independent of antigen. We are currently investigating the in vivo physiological role of this cytokine signaling pathway.